JP4406482B2 - Process for producing optically active 2-aminocyclohexanol derivative - Google Patents

Description

【０００８】
（式中Ｒ１、Ｒ２は、水素、アルキル基、アリール基およびアラルキル基のいずれかを示し、それぞれ同一でも異なっていても良い。但しＲ１およびＲ２の両者が水素の場合はのぞく。）で表される２−アミノシクロヘキサノール誘導体を光学活性アミノ酸誘導体、光学活性酒石酸アミド誘導体および光学活性リンゴ酸誘導体のいずれかを分割剤として光学分割することを特徴とする光学活性２−アミノシクロヘキサノール誘導体の製造法である。
【０００９】
【発明の実施の形態】
本発明で原料として使用する２−アミノシクロヘキサノール誘導体は、ヘキセンオキサイドをから対応するアミンの求核付加反応により合成するのが好ましい。
【００１０】
２−アミノシクロヘキサノール誘導体は、前記一般式（１）で表されるものが使用出来るが、ここで、Ｒ１、Ｒ２は、水素、炭素数１〜１２のアルキル基、フェニル基、トルイル基などのアリール基、ベンジル基などのアラルキル基が好ましい。さらに好ましくは、環状アルキル基であり、具体的には、２−（シクロプロピルアミノ）シクロヘキサノール、２−（シクロブチルアミノ）シクロヘキサノール、２−（ジヘキシルアミノ）シクロヘキサノール、２−（ジオクチルアミノ）シクロヘキサノールなどが挙げられる。
【００１１】
また、本発明で使用する分割剤は、光学活性アミノ酸誘導体、光学活性酒石酸誘導体および光学活性リンゴ酸誘導体のいずれかであり、公知の方法で合成することができる。これらの分割剤を用いることで、２−アミノシクロヘキサノール誘導体を高純度で、効率よく製造することが出来る。
【００１２】
ここであげられる分割剤としての光学活性アミノ酸誘導体としては光学活性α-アミノ酸誘導体が好ましく、さらに好ましいのは、光学活性αーアミノ酸の窒素上に１つまたは２つのアルキルスルホニル基、アリールスルホニル基、アラルキルスルホニル基、アルキルカルボニル基、アリールカルボニル基、アラルキルカルボニル基、アルコキシカルボニル基、アリールオキシカルボニル基あるいはアラルキルオキシカルボニル基を有する誘導体である。
【００１３】
具体的には、（＋）または（−）−Ｎ−アセチルメチオニン、（＋）または（−）−Ｎ−ホルミルイソロイシン、（＋）または（−）−Ｎ−アセチル−ｐ−メチルフェニルグリシン、（＋）または（−）−Ｎ−ベンゾイルフェニルグリシン、（＋）または（−）−Ｎ−アセチルロイシン、（＋）または（−）−Ｎ−tertブトキシカルボニルプロリン、（＋）または（−）−Ｎ−ベンジルオキシカルボニルフェニルグリシン、（＋）または（−）−Ｎ−パラトルエンスルホニルアスパラギン酸、（＋）または（−）−Ｎ−パラトルオイルフェニルグリシン、（＋）または（−）−Ｎ−パラニトロベンゾイルフェニルグリシン、（＋）または（−）−Ｎ−ベンゼンスルフォニルグルタミン酸、（＋）または（−）−Ｎ−ベンゼンスルホニルアスパラギン酸などが挙げられる。
【００１４】
光学活性酒石酸アミド誘導体としては、光学活性酒石酸アミド誘導体が一般式（２）
【００１５】
【化４】

【００１６】
（式中、Ｒ６、Ｒ７は水素、炭素数１から４のアルキル基、炭素数１から４のアルコキシル基、水酸基およびハロゲンのいずれかであり、同一でも異なっていても良い。ｎは０〜２を示す）で表される光学活性酒石酸アミド誘導体が好ましく、具体的には（＋）または（−）酒石酸モノ−Ｏ−クロロアニリド、（＋）または（−）酒石酸モノ−ｐ−クロロアニリド、（＋）または（−）酒石酸モノ−Ｏ−メトキシアニリド、（＋）または（−）酒石酸モノ−ｍ−メトキシアニリド、（＋）または（−）酒石酸−モノｐ−メトキシアニリド、（＋）または（−）酒石酸モノ−Ｏ−ニトロアニリド、（＋）または（−）酒石酸−モノｍ−ニトロアニリド、（＋）または（−）酒石酸モノ−２、４−ジクロロアニリド等があげられる。
【００１７】
光学活性リンゴ酸誘導体としては、（＋）または（−）リンゴ酸モノ−ｐ−ニトロアニリド等が好ましい。
【００１８】
２−アミノシクロヘキサノール誘導体を分割する際に用いる溶媒は、メタノール、エタノール、２−プロパノール等のアルコール類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、クロロホルム等のハロゲン化炭化水素、ジエチルエーテル、ジメチルエーテル、ジオキサン、テトラヒドロフラン等のエーテル類、ヘキサン、ペンタン、シクロヘキサン、１−ヘキセン、シクロヘキセン等の炭化水素類、アセトン、メチルエチルケトン等のケトン類、ジメチルスルホキシド、ジメチルホルムアミド等の極性溶媒類、水あるいはこれらの２種類以上の混合溶媒が好ましく、さらに好ましくは、メタノール、イソプロパノール、水等である。
【００１９】
２−アミノシクロヘキサノール誘導体と分割剤、上記の溶媒とを別々あるいは同時に反応容器に入れる。
【００２０】
反応温度は０℃から２００℃が好ましく、さらに好ましくは１０℃から８０℃で反応させる。反応で生成したジアステレオマー塩は、好ましくは−２０℃から８０℃、さらに好ましくは０℃から５０℃の範囲で晶出させ、結晶を濾別する。これら１連の操作を１回から１０回、望ましくは１回から３回行うことにより光学純度の高いジアステレオマー塩を得ることができる。得られたジアステレオマー塩を、酸あるいは塩基を用いることにより、分割剤と光学活性２−アミノシクロヘキサノール誘導体とに分離することができる。
【００２１】
ここで用いる酸はその酸性度が光学活性カルボン酸より強いものであればいずれでも良く、また同様に塩基は、２−アミノシクロヘキサノール誘導体よりも塩基性度が強いものであればいずれでも良い。一般的には、酸として塩酸、硫酸等の鉱酸を用いるのが好ましく、塩基としては水酸化ナトリウム、水酸化カリウム等の無機塩基を用いるのが好ましい。
【００２２】
分離された光学活性２−アミノシクロヘキサノール誘導体は公知の方法で精製を行い、化学的に純粋な光学活性２−アミノシクロヘキサノール誘導体を得ることができる。
【００２３】
【実施例】
以下、詳細は実施例で説明する。尚、光学純度はＨＰＬＣによる光学純度分析法で求めた。
【００２４】
実施例１
（２−（シクロプロピルアミノ）シクロヘキサノールの合成）
攪拌機、還流冷却管、温度計、滴下漏斗を備えた２Ｌ４口ナスフラスコに、ヘキセンオキサイド（東京化成（株）特級）８．２ｇ、メタノール１５５．２ｇを加え加熱還流させた。３０分間かけてシクロプロピルアミン６８．５ｇを滴下し、さらに２７時間加熱還流させた。得られた反応混合液を減圧濃縮し、真空乾燥することにより、１５１．１ｇの２−（シクロプロピルアミノ）シクロヘキサノールを得た。収率９７％、化学純度９６％であった。
【００２５】
（Ｌ−酒石酸ｐ−メトキシアニリドの合成）
還流冷却管、温度計を取りつけた１Ｌの筒型セパラブルフラスコに酒石酸６０ｇと無水酢酸１６３ｇを加え、よく攪拌しながら９６％硫酸０．５ｍｌを加えた。すぐに発熱し始め、内温が５０℃以上になり透明な溶液となった。そのまま攪拌を続け、内温が自然に室温に下がると白色結晶が析出してきた。この結晶を炉別し、トルエンで２回リスラリー洗浄を行って、ジアセチル酒石酸無水物７６ｇを得た。収率８６％。
【００２６】
このジアセチル酒石酸無水物を２Ｌの筒型セパラブルフラスコに仕込み、クロロホルム２００ｍｌを加えて攪拌し、そこへｐ−メトキシアニリン４８ｇをクロロホルム２００ｍｌに溶解した溶液をゆっくり滴下した。約１時間攪拌した後、水酸化ナトリウム４４ｇを水８００ｍｌで溶解した水酸化ナトリウム水溶液をゆっくり滴下して更に１時間攪拌した。この反応液を分液し、クロロホルム層を水２００ｍｌで洗浄し、先の水層と合わせた。この水層に９６％硫酸５９ｇを加えて酸析し、Ｌ−酒石酸ｐ−メトキシアニリド７１．７ｇを得た。収率８０％。
【００２７】
（分割）
温度計、攪拌機、還流冷却管を備えた４口２００ｍｌフラスコに、Ｌ−酒石酸−ｏ−メトキシアニリド２５．６ｇ、水４１．３ｇ、２−（シクロプロピルアミノ）シクロヘキサノール１５．５ｇを加え、７０度まで加熱し２時間攪拌しながら。塩が完全に溶解した後に、徐々に冷却し、２０℃で１８ｈｒ攪拌した。２．６ｇの水で洗浄し、遠心分離を行って、Ｗｅｔケーキを終夜加熱真空乾燥し、１１．０ｇのＤｒｙケーキを得た。（これを再結晶することにより＞９８％ｅ．ｅ．の光学純度２−（シクロプロピルアミノ）シクロヘキサノールを得た。）これを、温度計、攪拌機、還流冷却管を備えた４口１００ｍｌフラスコに入れ、水２０ｇを加え攪拌しながら１時間加熱した。塩が完全に溶解した後に、徐々に冷却し、２０℃で１６ｈｒ攪拌した。１ｇ水でリンスし、遠心分離を行って、Ｗｅｔケーキを得て、これを終夜加熱真空乾燥し、５．３ｇのＤｒｙケーキを得た。さらにこれを、温度計、攪拌機、還流冷却管を備えた４口５０ｍｌフラスコに入れ、水１２．７ｇを加え攪拌しながら１時間加熱した。塩が完全に溶解した後に、徐々に冷却し、２０℃で１５ｈｒ攪拌した。１ｇ水でリンスし、遠心分離を行って、Ｗｅｔケーキを得て、これを終夜加熱真空乾燥し、３．７ｇのＤｒｙケーキを得た。収率９％、Ｒ／Ｓ＝９２であった。
【００２８】
実施例２
このほかに、上記と同様に分割を行って、２−アミノシクロヘキサノール誘導体を分割するのに良好だった分割剤（○）、不適だった分割剤（×）を表１に示す。
【００２９】
（（＋）−ベンゾイルフェニルグリシンの合成）
（＋）−フェニルグリシン５９．０ｇ（０．３９モル）と水５１９．１ｇを１Ｌの三口フラスコに仕込み、液温を４５℃に昇温して攪拌し、４８％水酸化ナトリウム水溶液を加えて、ｐＨ１０に調製した。一方、ベンゾイルクロライド５４．８ｇ（０．３９モル）をトルエン８３．５ｇに溶解してベンゾイルクロライドのトルエン溶液を調製し、攪拌しながらＬ−フェニルグリシン水溶液中に滴下した。この間、温度は４４〜４７℃、ｐＨは４８％水酸化ナトリウム水溶液で１０．０にコントロールした。約２時間で滴下した後、さらに水酸化ナトリウム水溶液が入らなくなるまで約２時間反応を続けた。水酸化ナトリウムが仕込み（＋）−フェニルグリシンのほぼ２等量入り、ｐＨが変化しなくなったのを確認した後、バスを取り除き、室温中で放冷しながら、５０％硫酸４１ｇを約２時間で滴下し、室温でさらに１時間攪拌し続けた。ビーズ状に析出してきたＬ−ベンゾイルフェニルグリシンを遠心脱水し、トルエンでリンスしたのち、乾燥させ、（＋）−ベンゾイルフェニルグリシン９７．３ｇを得た。収率９７％。
【００３０】
（＋）−トルオイルフェニルグリシンは、（＋）−ベンゾイルフェニルグリシンの合成で使用したベンゾイルクロライドをパラメチルベンゾイルクロライドに変更した以外は上記と同様の方法で合成した。
【００３１】
（＋）−酒石酸ｏ−クロロアニリド、コハク酸モノ−（Ｓ）フェネチルアミドはオーガニック シンセシス コレクテイブ ボリューム ＩＶ（Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｅｓ ｃｏｌｌｅｃｔｉｖｅ Ｖｏｌｕｍｅ ＩＶ）ｐ２４２〜２４３を参照して合成した。
【００３２】
（＋）−２−フェニルプロピオン酸は、和光純薬工業（株）特級を用いた。
【００３３】
【表１】

【００３４】
【発明の効果】
本発明によれば、高い光学純度の２−アミノシクロヘキサノール誘導体を従来の方法より安定に製造することが出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an optically active 2-aminocyclohexanol derivative having high optical purity from a racemic 2-aminocyclohexanol derivative using a resolving agent.
[0002]
[Prior art]
As a means for obtaining an optically active 2-aminocyclohexanol derivative having high optical purity, for example, an optical resolution method using optically active tartaric acid or optically active diparatoluoyl tartaric acid is known (Japanese Patent Laid-Open No. 9-157258).
[0003]
[Problems to be solved by the invention]
The resolving agent used in JP-A-9-157258 has problems such as being difficult to recover because it is soluble in water, poor chemical stability under basic conditions, and expensive.
[0004]
[Means for Solving the Problems]
An object of the present invention is to provide a method for producing 2-aminocyclohexanol with higher optical purity by using a resolving agent rich in chemical stability.
[0005]
The inventors of the present invention designed a resolving agent that is considered to be chemically more stable than the resolving agent already reported, and as a result of diligently examining a method for optical resolution of a 2-aminocyclohexanol derivative using these, The present invention has been reached. In other words, the conventional optically active carboxylic acid and the optically active carboxylic acid that can be obtained at low cost can be easily chemically modified to solve the problems of conventional resolving agents. A method for producing a cyclohexanol derivative was found and the present invention was completed.
[0006]
That is, the present invention relates to the general formula (1)
[0007]
[Chemical 3]

[0008]
(Wherein R1 and R2 each represent hydrogen, an alkyl group, an aryl group or an aralkyl group, which may be the same or different, except when both R1 and R2 are hydrogen). A method for producing an optically active 2-aminocyclohexanol derivative, wherein the 2-aminocyclohexanol derivative is optically resolved using any one of an optically active amino acid derivative, an optically active tartaric acid amide derivative and an optically active malic acid derivative as a resolving agent It is.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The 2-aminocyclohexanol derivative used as a raw material in the present invention is preferably synthesized from hexene oxide by a nucleophilic addition reaction of the corresponding amine.
[0010]
As the 2-aminocyclohexanol derivative, those represented by the general formula (1) can be used. Here, R1 and R2 are hydrogen, an alkyl group having 1 to 12 carbon atoms, a phenyl group, a toluyl group, and the like. Aralkyl groups such as aryl groups and benzyl groups are preferred. More preferably, it is a cyclic alkyl group, and specifically, 2- (cyclopropylamino) cyclohexanol, 2- (cyclobutylamino) cyclohexanol, 2- (dihexylamino) cyclohexanol, 2- (dioctylamino). And cyclohexanol.
[0011]
The resolving agent used in the present invention is any one of an optically active amino acid derivative, an optically active tartaric acid derivative and an optically active malic acid derivative, and can be synthesized by a known method. By using these resolving agents, 2-aminocyclohexanol derivatives can be produced with high purity and efficiency.
[0012]
The optically active amino acid derivative as the resolving agent mentioned here is preferably an optically active α-amino acid derivative, and more preferably one or two alkylsulfonyl groups, arylsulfonyl groups on the nitrogen of the optically active α-amino acid, A derivative having an aralkylsulfonyl group, an alkylcarbonyl group, an arylcarbonyl group, an aralkylcarbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group.
[0013]
Specifically, (+) or (−)-N-acetylmethionine, (+) or (−)-N-formylisoleucine, (+) or (−)-N-acetyl-p-methylphenylglycine, ( +) Or (-)-N-benzoylphenylglycine, (+) or (-)-N-acetylleucine, (+) or (-)-N-tert-butoxycarbonylproline, (+) or (-)-N -Benzyloxycarbonylphenylglycine, (+) or (-)-N-paratoluenesulfonylaspartic acid, (+) or (-)-N-paratoluoylphenylglycine, (+) or (-)-N-para Nitrobenzoylphenylglycine, (+) or (-)-N-benzenesulfonyl glutamic acid, (+) or (-)-N-benzenesulfonylaspara Examples include formic acid.
[0014]
As the optically active tartaric acid amide derivative, the optically active tartaric acid amide derivative is represented by the general formula (2).
[0015]
[Formula 4]

[0016]
(Wherein R6 and R7 are any one of hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group and a halogen, and n may be the same or different. (+) Or (−) tartaric acid mono-O-chloroanilide, (+) or (−) tartaric acid mono-p-chloroanilide, ( +) Or (−) tartaric acid mono-O-methoxyanilide, (+) or (−) tartaric acid mono-m-methoxyanilide, (+) or (−) tartaric acid-mono p-methoxyanilide, (+) or (− And tartaric acid mono-O-nitroanilide, (+) or (−) tartaric acid-mono m-nitroanilide, (+) or (−) tartaric acid mono-2,4-dichloroanilide and the like.
[0017]
As the optically active malic acid derivative, (+) or (−) malic acid mono-p-nitroanilide is preferable.
[0018]
Solvents used for dividing the 2-aminocyclohexanol derivative are alcohols such as methanol, ethanol and 2-propanol, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane and chloroform, Ethers such as diethyl ether, dimethyl ether, dioxane and tetrahydrofuran, hydrocarbons such as hexane, pentane, cyclohexane, 1-hexene and cyclohexene, ketones such as acetone and methyl ethyl ketone, polar solvents such as dimethyl sulfoxide and dimethylformamide, water Or these 2 or more types of mixed solvents are preferable, More preferably, they are methanol, isopropanol, water, etc.
[0019]
A 2-aminocyclohexanol derivative, a resolving agent, and the above solvent are put into a reaction vessel separately or simultaneously.
[0020]
The reaction temperature is preferably 0 ° C to 200 ° C, more preferably 10 ° C to 80 ° C. The diastereomeric salt formed by the reaction is preferably crystallized in the range of −20 ° C. to 80 ° C., more preferably 0 ° C. to 50 ° C., and the crystals are separated by filtration. A diastereomeric salt with high optical purity can be obtained by performing these one series of operations 1 to 10 times, preferably 1 to 3 times. The obtained diastereomeric salt can be separated into a resolving agent and an optically active 2-aminocyclohexanol derivative by using an acid or a base.
[0021]
The acid used here may be any acid as long as its acidity is stronger than that of the optically active carboxylic acid. Similarly, the base may be any acid as long as its basicity is stronger than that of the 2-aminocyclohexanol derivative. In general, a mineral acid such as hydrochloric acid or sulfuric acid is preferably used as the acid, and an inorganic base such as sodium hydroxide or potassium hydroxide is preferably used as the base.
[0022]
The separated optically active 2-aminocyclohexanol derivative can be purified by a known method to obtain a chemically pure optically active 2-aminocyclohexanol derivative.
[0023]
【Example】
Details will be described below in Examples. The optical purity was determined by an optical purity analysis method using HPLC.
[0024]
Example 1
(Synthesis of 2- (cyclopropylamino) cyclohexanol)
To a 2 L 4-neck eggplant flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, 8.2 g of hexene oxide ( Tokyo Kasei Co., Ltd.) and 155.2 g of methanol were added and heated to reflux. 68.5 g of cyclopropylamine was added dropwise over 30 minutes, and the mixture was further heated to reflux for 27 hours. The obtained reaction mixture was concentrated under reduced pressure and vacuum dried to obtain 151.1 g of 2- (cyclopropylamino) cyclohexanol. The yield was 97% and the chemical purity was 96%.
[0025]
(Synthesis of L-tartaric acid p-methoxyanilide)
To a 1 L cylindrical separable flask equipped with a reflux condenser and a thermometer, 60 g of tartaric acid and 163 g of acetic anhydride were added, and 0.5 ml of 96% sulfuric acid was added with good stirring. Heat generation started immediately, and the internal temperature reached 50 ° C. or higher, resulting in a transparent solution. Stirring was continued as it was, and when the internal temperature naturally decreased to room temperature, white crystals were precipitated. The crystals were separated by furnace and reslurry washed twice with toluene to obtain 76 g of diacetyltartaric anhydride. Yield 86%.
[0026]
This diacetyltartaric anhydride was charged into a 2 L cylindrical separable flask, 200 ml of chloroform was added and stirred, and a solution of 48 g of p-methoxyaniline dissolved in 200 ml of chloroform was slowly added dropwise thereto. After stirring for about 1 hour, a sodium hydroxide aqueous solution in which 44 g of sodium hydroxide was dissolved in 800 ml of water was slowly added dropwise, and the mixture was further stirred for 1 hour. The reaction solution was separated, and the chloroform layer was washed with 200 ml of water and combined with the previous aqueous layer. The aqueous layer was acidified by adding 59 g of 96% sulfuric acid to obtain 71.7 g of p-methoxyanilide L-tartaric acid. Yield 80%.
[0027]
(Split)
To a 4-neck 200 ml flask equipped with a thermometer, stirrer and reflux condenser, 25.6 g of L-tartaric acid-o-methoxyanilide, 41.3 g of water, 15.5 g of 2- (cyclopropylamino) cyclohexanol were added. While stirring to 2 degree, stirring for 2 hours. After the salt was completely dissolved, it was gradually cooled and stirred at 20 ° C. for 18 hours. The wet cake was washed with 2.6 g of water and centrifuged, and the wet cake was heated and dried in vacuum overnight to obtain 11.0 g of a dry cake. (This was recrystallized to obtain> 98% ee optical purity 2- (cyclopropylamino) cyclohexanol.) This was a 4-neck 100 ml flask equipped with a thermometer, stirrer and reflux condenser. Then, 20 g of water was added and heated for 1 hour with stirring. After the salt was completely dissolved, the salt was gradually cooled and stirred at 20 ° C. for 16 hours. After rinsing with 1 g water and centrifuging, a wet cake was obtained, and this was heated and vacuum dried overnight to obtain 5.3 g of a dry cake. Furthermore, this was put into a 4-neck 50 ml flask equipped with a thermometer, a stirrer and a reflux condenser, and 12.7 g of water was added and heated for 1 hour with stirring. After the salt was completely dissolved, it was gradually cooled and stirred at 20 ° C. for 15 hours. After rinsing with 1 g water and centrifuging, a wet cake was obtained, and this was heated and vacuum dried overnight to obtain 3.7 g of a dry cake. The yield was 9% and R / S = 92.
[0028]
Example 2
In addition, Table 1 shows the resolving agent (◯) that was good for resolving the 2-aminocyclohexanol derivative by dividing in the same manner as described above, and the resolving agent (x) that was not suitable for resolving.
[0029]
(Synthesis of (+)-benzoylphenylglycine)
(+)-Phenylglycine 59.0 g (0.39 mol) and 519.1 g of water were charged into a 1 L three-necked flask, the temperature was raised to 45 ° C. and stirred, and a 48% sodium hydroxide aqueous solution was added. PH 10 was adjusted. On the other hand, 54.8 g (0.39 mol) of benzoyl chloride was dissolved in 83.5 g of toluene to prepare a toluene solution of benzoyl chloride, which was dropped into an aqueous solution of L-phenylglycine while stirring. During this time, the temperature was controlled at 44 to 47 ° C., and the pH was controlled at 10.0 with a 48% aqueous sodium hydroxide solution. After dropwise addition in about 2 hours, the reaction was continued for about 2 hours until no further sodium hydroxide aqueous solution entered. Sodium hydroxide was charged and approximately 2 equivalents of (+)-phenylglycine was added. After confirming that the pH did not change, the bath was removed and 41 g of 50% sulfuric acid was added for about 2 hours while cooling at room temperature. The mixture was added dropwise at room temperature and stirred for another hour at room temperature. L-benzoylphenylglycine precipitated in the form of beads was centrifuged and dehydrated, rinsed with toluene, and then dried to obtain 97.3 g of (+)-benzoylphenylglycine. Yield 97%.
[0030]
(+)-Toluoylphenylglycine was synthesized in the same manner as above except that the benzoyl chloride used in the synthesis of (+)-benzoylphenylglycine was changed to paramethylbenzoyl chloride.
[0031]
(+) - tartaric acid o- chloroanilide, monosuccinic acid - (S) phenethylamide was synthesized with reference to Organic Synthesis Korekuteibu volume IV (Organic Syntheses collective Volume IV) p242~243.
[0032]
(+)-2-Phenylpropionic acid used Wako Pure Chemical Industries special grade.
[0033]
[Table 1]

[0034]
【The invention's effect】
According to the present invention, a high optical purity 2-aminocyclohexanol derivative can be produced more stably than the conventional method.

Claims (5)

General formula (1)

(Wherein R1 and R2 each represent hydrogen, an alkyl group, an aryl group or an aralkyl group, which may be the same or different, except when both R1 and R2 are hydrogen). that process for producing an optically active 2-aminocyclohexanol derivative, which comprises optically resolving the 2-aminocyclohexanol derivative to any of optically active phenylglycine derivative and optically active tartaric acid amide derived material as a resolving agent. The method for producing an optically active 2-aminocyclohexanol derivative according to claim 1, wherein the optically active phenylglycine derivative is an optically active α- phenylglycine derivative. The optically active α- phenylglycine derivative is an alkylsulfonyl group, arylsulfonyl group, aralkylsulfonyl group, alkylcarbonyl group, arylcarbonyl group, aralkylcarbonyl group, alkoxycarbonyl group, aryloxycarbonyl group on the nitrogen of the optically active α-phenylglycine. And the method for producing an optically active 2-aminocyclohexanol derivative according to claim 2, which has any one or two of aralkyloxycarbonyl groups. The optically active tartaric acid amide derivative has the general formula (2)

(Wherein R6 and R7 are any one of hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group and a halogen, and n may be the same or different. The method for producing an optically active 2-aminocyclohexanol derivative according to claim 1, wherein the optically active tartaric acid amide derivative is represented by the formula: 5. The R 1 of the 2-aminocyclohexanol derivative represented by the general formula (1) is a cyclic alkyl group having 3 to 6 carbon atoms, and R 2 is hydrogen. A process for producing an optically active 2-aminocyclohexanol derivative.